Permeability of fluid-phase phospholipid bilayers: Assessment and useful correlations for permeability screening and other applications

Permeability data (P^lip/w) for liquid crystalline phospholipid bilayers composed of egg lecithin and dimyristoylphosphatidylcholine (DMPC) are analyzed in terms of a mathematical model that accounts for free surface area and chain-ordering effects in the bilayer as well as size and lipophilicity of the permeating species. Free surface area and chain ordering are largely determined by temperature and cholesterol content of the membrane, molecular size is represented by molecular weight, and lipophilicity of the barrier region is represented by the 1,9-decadiene/water partition coefficient, following earlier work by Xiang, Anderson, and coworkers. A correlating variable χ = MWⁿσ/(1-σ) is used to link the results from different membrane systems, where different values of n are tried, and σ denotes a reduced phospholipid density. The group (1-σ)/σ is a measure of free surface area, but can also be interpreted in terms of free volume. A single exponential function of χ is developed that is able to correlate 39 observations of P^lip/w for different compounds in egg lecithin at low density, and 22 observations for acetic acid in DMPC at higher densities, spanning nine orders of magnitude to within an rms error for log ₁₀ P^lip/w of 0.20. The best fit found for n = 0.87 ultimately makes χ much closer to the ratio of molecular to free volumes than surface areas. The results serve as a starting point for estimating passive permeability of cell membranes to nonionized solutes as a function of temperature and cholesterol content of the membrane.